2-(Phenylseleno)-1,4-dioxane as a Convenient Reagent for the Selective ­Protection of Alcohols as 1,4-Dioxan-2-yl Ethers

Abstract

Using an O,Se-acetal, activated by copper(II) chloride, a new, simple and chemoselective method for the preparation of differently substituted alcohols as 1,4-dioxan-2-yl derivatives has been accomplished.

Key words

acetals - alcohols - copper - protecting groups - selenium

References and Notes

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11

Other metal salts such as ZnCl₂, Zn(OTf)₂, CoCl₂, NiCl₂, CeCl₃, and FeCl₃ did not give any trace of product 8a. Product 8a was also obtained in moderate yield by activation with silver triflate, NIS, or NBS.

12

Protection of Alcohols; General Procedure
To a mixture of the alcohol 8 (1 mmol), the O,Se-acetal 7 (1.4 mmol) and activated 3 Å MS (0.10 g) in dry EtOAc or THF (15 mL), dry CuCl₂ (2.8 mmol) was added at r.t. The mixture was stirred under inert atmosphere until the starting alcohol has completely disappeared (monitored by TLC). Reaction times ranged from 2-23 h. A 30% NH₄OH solution (0.4 mL) was added and stirring was continued for few minutes. After addition of anhyd Na₂SO₄, the reaction mixture was filtered through a Celite pad and the filtrate concentrated. After chromatography on silica gel column, compound 9 were obtained in a pure form. Physical and spectral data of compound 9d are reported below whereas compound 9b is described in the Supporting Information.
Methyl N -( tert -Butoxycarbonyl)- O -1,4-dioxan-2-yl-serinate (9d)
Yield 72%; oil; 1:1 mixture of diastereomers. ^¹H NMR (200 MHz, CDCl₃): δ = 5.57 (d, 1 H, J = 8.6 Hz), 5.39 (d, 1 H, J = 9.2 Hz), 4.57-4.48 (m, 4 H), 4.21-4.19 (m, 2 H), 4.05-3.81 (m, 4 H), 3.79 (s, 3 H), 3.76 (s, 3 H), 3.73-3.44 (m, 10 H), 1.45 (s, 18 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 170.9, 170.7, 155.4 (2 C), 96.1, 95.7, 79.9, 79.8, 68.5, 68.4, 68.2, 67.8, 60.0 (4 C), 61.6, 61.2, 53.8, 53.6, 52.4, 52.3, 28.2 (6 C). GC-MS (EI): m/z (%, first diastereomer) = 246 (2) [M - 59]⁺, 189 (21), 146 (100), 133 (59), 101 (15), 87 (63), 57 (46); m/z (%, second diastereomer) = 246 (3) [M - 59]⁺, 189 (30), 146 (100), 133 (69), 101 (18), 87 (62), 57 (48). Anal. Calcd for C₁₃H₂₃NO₇: C, 51.14; H, 7.59; N, 4.59. Found: C, 51.47; H, 7.87; N, 4.33.

13

Selective protection of phenolic alcohols 10a-c was obtained as described above for substrates 8. Physical and spectral data of compounds 11a-c are reported below.
4-[(1,4-Dioxan-2-yloxy)methyl]phenol (11a)
Yield 80%; oil. FT-IR (KBr): 3341, 2919, 1615, 1595, 1266, 1143, 1079, 1036, 903, 877 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 8.05 (s, 1 H), 7.25 (d, 2 H, J = 8.1 Hz), 6.84 (d, 2 H, J = 8.1 Hz), 4.80 (d, 1 H, J = 11.5 Hz), 4.67 (t, 1 H, J = 2.6 Hz), 4.52 (d, 1 H, J = 11.5 Hz), 4.24-4.11 (m, 1 H), 3.83-3.72 (m, 3 H), 3.70-3.56 (m, 2 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 155.8, 129.9 (2 C), 128.8, 115.3 (2 C), 94.2, 69.1, 68.9, 66.2, 61.2. GC-MS (EI): m/z (%) = 210 (2) [M⁺], 120 (20), 107 (100), 87 (2), 77 (7). Anal. Calcd for C₁₁H₁₄O₄: C, 62.85; H, 6.71. Found: C, 63.07; H, 6.97.
5-[(1,4-Dioxan-2-yloxy)methyl]benzene-1,3-diol (11b)
Yield 76%; mp 116-119 ˚C. FT-IR (KBr): 3294, 2859, 1630, 1600, 1497, 1366, 1303, 1173, 1139, 1056, 978, 902, 863, 834 cm^-¹. ^¹H NMR (200 MHz, acetone-d ₆): δ = 8.20 (s, 2 H), 6.38-6.30 (m, 2 H), 6.29-6.20 (m, 1 H), 4.61(d, 1 H, J = 12.1 Hz), 4.58 (t, 1 H, J = 3.1 Hz), 4.38 (d, 1 H, J = 12.1 Hz), 4.04-3.90 (m, 1 H), 3.69-3.40 (m, 5 H). ^¹³C NMR (50 MHz, acetone-d ₆): δ = 159.6 (2 C), 141.6, 106.9 (2 C), 102.6, 95.9, 69.6, 66.9, 62.3. Anal. Calcd for C₁₁H₁₄O₅: C, 58.42; H, 6.24. Found: C, 58.68; H, 6.51.
2-[2-(1,4-Dioxan-2-yloxy)ethyl]phenol (11c)
Yield 72%; mp 726-74 ˚C. FT-IR (KBr): 3267, 2926, 2870, 1594, 1505, 1455, 1265, 1143, 1053, 909, 866, 757 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 7.40 (s, 1 H), 7.20-7.02 (m, 2 H), 6.95-6.76 (m, 2 H), 4.57 (t, 1 H, J = 2.6 Hz), 4.12 (ddd, 1 H, J = 9.1, 6.5, 3.9 Hz), 3.98-3.84 (m, 1 H), 3.77-3.60 (m, 5 H), 3.59-3.42 (m, 1 H), 3.01 (ddd, 1 H, J = 14.9, 7.8, 3.7 Hz), 2.87 (ddd, 1 H, J = 14.9, 6.4, 3.6 Hz). ^¹³C NMR (50 MHz, CDCl₃): δ = 155.2, 130.8, 128.3, 126.2, 120.4, 117.0, 95.8, 69.6, 68.4, 66.0, 61.1, 32.3. GC-MS (EI): m/z (%) = 224 (15) [M⁺], 138 (100), 121 (96), 107 (29), 91 (32), 87 (48), 77 (29). Anal. Calcd for C₁₂H₁₆O₄: C, 64.27; H, 7.19. Found: C, 64.59; H, 7.41.

14

Selective Protection of Diol 10e
To a mixture of the diol 10e (0.12 g. 0.8 mmol), the O,Se-acetal 7 (0.23 g, 0.96 mmol) and activated 3 Å MS (0.10 g) in dry THF (12 mL), dry CuCl₂ (0.13 g, 0.96 mmol) was added at r.t. under inert atmosphere. After 9 h a 30% NH₄OH solution (0.3 mL) was added and stirring was continued for few minutes. After addition of anhyd Na₂SO₄, the reaction mixture was filtered through a Celite pad and the filtrate concentrated. After chromatography on silica gel column, 0.10 g compound 11e and 0.05 g of the starting diol 10e were obtained in a pure form. Physical and spectral data of 11e are reported below.
3-(1,4-Dioxan-2-yloxy)-1-phenylpropan-1-ol (11e)
Yield 89%; oil. FT-IR (KBr): 3449, 2880, 1455, 1266, 1147, 1052, 870, 757 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ (1:1 mixture of diastereomers) = 7.45-7.20 (m, 10 H), 4.97-4.86 (m, 2 H), 4.59-4.50 (m, 2 H), 4.08-3.85 (m, 4 H), 3.76-3.45 (m, 12 H), 3.15 (s, 2 H), 2.15-1.97 (m, 4 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 144.0 (2 C), 120.3 (4 C), 127.3 (2 C), 125.7 (4 C), 96.0, 95.9, 72.4, 71.9, 68.7 (2 C), 66.0, 65.9, 65.8, 65.6, 61.8, 61.4, 38.5 (2 C). GC-MS (EI): m/z (%) = 193 (19) [M - 45]⁺, 176 (15), 151 (24), 133 (36), 117 (26), 107 (100), 91 (23), 87 (30), 77 (29), 57 (14). Anal. Calcd for C₁₃H₁₈O₄: C, 65.53; H, 7.61. Found: C, 65.78; H, 7.70.

15

Preliminary experiments carried out on compounds 8a and 8b with 2-(phenylseleno)tetrahydrofuran gave the corresponding tetrahydrofuranyl ethers in good yields, whereas compounds 8c and 10a gave lower yields.